Mammalian animals need to incorporate nutrients from an external source, and many transport proteins are known to exist in cells. Peptide transporters (peptide transport proteins) transport peptides, and many have been found to date (for example, Non-Patent Documents 1, 2, and 3; and Patent Documents 1, 2, and 3). Peptide transporters can be classified into proteins that import peptides into cells, and proteins that export peptides from cells. They can also be classified by the difference of the energy sources used in transport. Proton-driven peptide transporters, which carry out transport by utilizing the difference in proton concentrations between the inside and outside of a cell, belong to the PTR family (Non-Patent Document 3). Peptide transporters that carry out transport using ATP in the body belong to the ABC family (Non-Patent Document 4).
It has been reported that peptide transporters are involved in the transport of not only small-molecule peptides such as dipeptides and tripeptides, but also pharmaceutical agents such as β-lactam antibiotics and ACE inhibitors (Non-Patent Documents 5, 6, 7, 8, 9, and 10).
PepT1 and PepT2 are proton-driven peptide transporters which contribute to the absorption of proteins and the maintenance of peptidic nitrogen sources through uptake of small-molecule peptides into cells. PepT1 and PepT2 are 12-transmembrane proteins, consisting of 708 and 729 amino acids, respectively (Non-Patent Documents 1, 2, and 11).
PepT1 and PepT2 have also been reported to transport pharmaceuticals such as β-lactam antibiotics and bestatin (Non-Patent Documents 12, 13, and 14).
PepT1 is mainly expressed in the small intestine, and its expression in kidney and pancreas has also been confirmed. PepT2 expression has been confirmed in kidney, brain, lung, and spleen. PepT1 and PepT2 have been reported to be localized in the small intestine, as well as in the brush border membrane of renal tubular epithelial cells (Non-Patent Documents 15, 16, 17, and 11).
Furthermore, overexpression of PepT1 in the cell membranes of human pancreatic ductal carcinoma cell lines (Non-Patent Document 18), and PepT2 mRNA expression in human pancreatic ductal carcinoma cell lines (Non-Patent Document 19) have been reported. However, the involvement of PepT1 and PepT2 in cancer cell growth is not clear, and the question of whether inhibiting the functions of PepT1 and PepT2 will affect cancer cell proliferation has never been discussed.    [Patent Document 1] Japanese Patent Application Kokai Publication No. (JP-A) H6-261761 (unexamined, published Japanese patent application)    [Patent Document 2] JP-A H11-172    [Patent Document 3] U.S. Pat. No. 5,849,525    [Non-Patent Document 1] J. Biol. Chem., 270(12):6456-6463, (1995)    [Non-Patent Document 2] Biochim. Biophys. Acta., 1235:461-466, (1995)    [Non-Patent Document 3] Mol. Microbiol., Vol. 16, p825, (1995)    [Non-Patent Document 4] Annu. Rev. Cell. Biol., Vol. 8, p67, (1992)    [Non-Patent Document 5] Ganaphthy, Leibach., Curr. Biol. 3, 695-701, (1991)    [Non-Patent Document 6] Nakashima et al., Biochem. Pharm. 33, 3345-3352, (1984)    [Non-Patent Document 7] Friedman, Amidon., Pharm. Res., 6, 1043-1047, (1989)    [Non-Patent Document 8] Okano et al., J. Biol. Chem., 261, 14130-14134, (1986)    [Non-Patent Document 9] Muranushi et al., Pharm. Res., 6, 308-312, (1989)    [Non-Patent Document 10] Friedman, Amidon., J. Control. Rel., 13, 141-146, (1990)    [Non-Patent Document 11] Terada, Inui, Tanpakusitsu Kakusan Kouso (Proteins, Nucleic acids, Enzymes), Vol. 46, No. 5, (2001)    [Non-Patent Document 12] Saito, H. et al., J. Pharmacol. Exp. Ther., 275, 1631-1637, (1995)    [Non-Patent Document 13] Saito, H. et al., Biochim. Biophys. Acta., 1280, 173-177, (1996)    [Non-Patent Document 14] Terada, T. et al., J. Pharmacol. Exp. Ther., 281, 1415-1421 (1997)    [Non-Patent Document 15] Ogihara, H. et al., Biochem. Biophys. Res. Commun. 220, 848-852, (1996)    [Non-Patent Document 16] Takahashi, K. et al., J. Pharmacol. Exp. Ther., 286, 1037-1042 (1998)    [Non-Patent Document 17] Hong, S. et al., Am. J. Physiol. Renal. Physiol., 276, F658-F665 (1999)    [Non-Patent Document 18] Cancer Res., 58, 519-525, (1998)    [Non-Patent Document 19] Millennium World Congress of Pharmaceutical Sciences, (2000)